Acid-Triggered Release of Native Gemcitabine Conjugated in Polyketal Nanoparticles for Enhanced Anticancer Therapy

Abstract

Nucleoside analogue drugs are widely used in cancer therapy and antiviral therapy, while fast metabolism, drug resistance, and severe side effects significantly limit their clinical applications. To address these issues, a variety of ester- and amide-linked prodrugs and their nanoparticulate formulations have been devised. However, most of these prodrugs suffer from inefficient transformation to native drugs in tumor. Here, we report an approach to conjugate gemcitabine, a kind of anticancer nucleoside drug and widely used to treat cancers, to polyketal backbone via pH-sensitive ketal linkage, and prepared gemcitabine-containing polyketal prodrug nanoparticles with minimal drug release under physiological conditions and acid-triggerable release of native gemcitabine. Intracellular and intratumoral degradation of the pH-sensitive gemcitabine-containing polyketal prodrug and incorporation of gemcitabine into DNA were confirmed by confocal microscopy using EdU, an analogue of gemcitabine. One single intravenous injection of these gemcitabine-containing polyketal prodrug nanoparticles demonstrated notable anticancer efficacy in the A2780 ovarian xenograft tumor model with increased survival rate and good safety. Our approach can be adopted for other diol nucleoside analogues to synthesize pH-sensitive nucleoside-polyketal prodrugs for developing anticancer and antiviral formulations.

Dually Enzyme- and Acid-Triggered Self-Immolative Ketal Glycoside Nanoparticles for Effective Cancer Prodrug Monotherapy

“…Given acetone-based ketal-linked prodrugs can be obtained from acid-catalyzed reactions of alcohols and isopropenyl ethers − and that substitution at the 1-position of glucose does not affect the affinity of glucose for its transporters, , we began by carrying out reactions of ETP with isopropenyl 2,3,4,6-tetra-O-benzyl-α- or β- d -glucopyranoside and subsequent hydrogenolysis to remove the benzyl protecting groups (Figure , Schemes S1–S4). For most ETP prodrugs, nucleophilic substitution under basic conditions proceeds at the phenol group of the ETP molecule.…”

Nanotechnology for COVID-19: Therapeutics and Vaccine Research

“…Several such combinations for novel coronavirus treatment are documented in the WHO landscape information (Table ). Nanocarriers are also intrinsically very useful for the delivery of multiple drugs with different physicochemical properties promising the full potential of combination therapies. , The flexibility offered by a variety of nanomaterials and fabrication techniques enables the design of drug combinations loaded in nanocarriers with excellent control in preserving synergistic drug ratios, overlapping pharmacokinetics, and reducing combination allied side-effects . Various nanocarrier strategies are described for the co-encapsulation of both hydrophobic and hydrophilic drugs (Figure ), achieving the sequential release of two drugs, ratiometric loading and controlled release of three drug candidates, codelivery of RNAi/plasmidDNA + chemotherapeutics, and codelivery of siRNA + micoRNA. − A nanosuspension of LNPs loaded with three ARVs drugs (two hydrophobic: lopinavir and ritonavir and one hydrophilic: tenofovir) has been formulated to overcome the lymph node drug insufficiency of the oral combination of these drugs.…”

Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles

“…1 With the aim of overcoming these challenging issues, prodrug approaches have been largely investigated and their relevance is well confirmed by the observation that prodrugs represent up to 10 % of all the new drug molecules approved by the FDA over the 2008-2017 period. 2 Prodrugs can be obtained by chemical modification of the parent molecule with small moieties (e.g., ionizable groups which increase aqueous drug solubility), 3,4 but derivatization with lipids, 4-6 peptides 7 and polymers 4,[8][9][10] has also been proposed. The latter enables to protect the drug from the degradation and/or to achieve a controlled and sustained drug release.…”